TXNIP Promots ROS-inducing DNA Damage To Reverse Chemotherapy Resistance In Triple Negative Breast Cancer

Background: Triple-negative breast cancer(TNBC)is the most malignant molecular type of breast cancer and lacks the expression of estrogen and progesterone receptor(ER/PR)and human epidermal growth factor receptor-2(HER2).Chemotherapy is the main treatment for TNBC patients.However,commonly used clinical chemotherapy drugs such as doxorubicin(DOX)are very easy to develop resistance.Therefore,screening out molecules related to chemotherapy resistance and studying their specific mechanisms are of great clinical significance to improve the chemotherapeutic efficacy of TNBC patients.Thioredoxin interacting protein(TXNIP)is a metabolic-related protein,and has a tumor suppressor effect on the occurrence and development of a variety of malignant tumors such as lung and breast cancer,but TXNIP regulates the progression of TNBC and its specific role in chemotherapy resistance has not been reported.Objectives: To study the specific mechanism of TXNIP affecting the drug resistance of TNBC;To explore the chemotherapeutic effect based on 10058-F4 and DOX combination for resistance to TNBC.Methods: The effects of TXNIP on the proliferation and apoptosis of TNBC drug-resistant cells in vivo and in vitro were detected by CCK-8,clone formation,flow cytometry and tumor formation in nude mice;Western blotting,immunofluorescence-laser confocal microscope,DHE fluorescent probe-flow cytometry were used to detect the accumulation of reactive oxygen species(ROS)and DNA damage in TNBC drug-resistant cells mediated by TXNIP;Ed U,flow cytometry,subcutaneous tumor formation and other experiments and the calculation of the combination index were used to analyse the combination of c-Myc inhibitor 10058-F4 and DOX for drug-resistant cells.Results: TXNIP inhibits the proliferation of TNBC drug-resistant cells and induces apoptosis.TXNIP induces the production of ROS in drug-resistant cells and induces DNA damage,and it increases the level of DNA damage index molecule γ-H2 AX in a time and dose-dependent manner.Moreover,ROS scavenger pretreatment can block the DNA damage induced by TXNIP and partially restored the resistance of TNBC resistant cells to DOX.In addition,the small molecule c-Myc inhibitor10058-F4 promoted the expression of TXNIP,increased the production of ROS in cells,and significantly inhibit the proliferation of TNBC resistant cells and the growth of transplanted tumors in nude mice in vivo and in vitro.Conclusions: 1.TXNIP increased the level of ROS in drug-resistant cells and promote the accumulation of DNA damage,so as to reverse the chemoresistance of TNBC;2.Small molecule inhibitor 10058-F4 can up regulate TXNIP and combined with DOX can enhance the cytotoxicity of chemotherapy drugs.